EP0285284B1

EP0285284B1 - N-phenethylaminoalkyl-benzamide anti-arrhythmia agents

Info

Publication number: EP0285284B1
Application number: EP88302270A
Authority: EP
Inventors: Peter Edward Dr. Cross; John Edmund Dr. Arrowsmith
Original assignee: Pfizer Ltd
Current assignee: Pfizer Ltd
Priority date: 1987-03-20
Filing date: 1988-03-16
Publication date: 1991-05-15
Anticipated expiration: 2008-03-16
Also published as: EP0285284A3; JPS63255258A; ATE63541T1; GR3001955T3; ES2035915T3; GB8706662D0; DE3862791D1; PT87005B; EP0285284A2; DK148288D0; PT87005A; DK148288A

Abstract

Compounds of the formula: <CHEM> and their pharmaceutically acceptable salts, wherein R<1> and R<5> are each independently C1-C4 alkyl; R<2> and R<3> are each independently H or C1-C4 alkyl; R<4> is H or C1-C4 alkoxy, and n is 2, 3 or 4, are anti-arrhythmia agents useful for the treatment of cardiac conditions.

Description

This invention relates to certain N-phenethylaminoalkyl-benzamide derivatives which are anti-arrhythmia agents useful for the treatment of cardiac conditions.
The compounds of the invention prolong the duration of the action potential in cardiac muscle and conducting tissue, and thereby increase refractoriness to premature stimuli. Thus, they are Class III anti-arrhythmic agents according to the classification of Vaughan Williams (Anti-Arrhythmic Action, E. M. Vaughan Williams, Academic Press, 1980). They are effective in atria, ventricles and conducting tissue both in vitro and in vivo and are therefore useful for the prevention and treatment of a wide variety of ventricular and supraventricular arrhythmias including atrial and ventricular fibrillation. Because they do not alter the speed at which impulses are conducted, they have less propensity than current drugs (mostly Class I) to precipitate or aggravate arrhythmias, and they also produce less neurological side effects. Some of the compounds also have positive inotropic activity and therefore are particularly beneficial in patients with impaired cardiac pump function.
Thus the invention provides compounds of the formula :
and their pharmaceutically acceptable salts, wherein R¹ and R⁵ are each independently C₁-C₄ alkyl ;

R² and R³ are each independently H or C_l-C₄ alkyl ;
R⁴ is H or C_i-C₄ alkoxy,
and n is 2, 3 or 4.

The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts formed from acids which form non-toxic salts such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts. Some of the compounds may also form metal salts, particularly alkaline earth and alkali metal salts. Examples include the sodium and potassium salts.
R¹ and R⁵ are preferably both CH₃, R² is preferably CH₃ or CH₂CH₃, R³ is preferably H, R⁴ is preferably H or OCH₃ and n is preferably 2.
Thus in one particular and preferred aspect, the invention provides the compound of formula (I) wherein R¹ is CH₃, R² is CH₃, R³ is H, R⁴ is methoxy attached at the 2-position of the phenyl ring and R⁵ is CH₃, the group -NHS0₂R⁵ being attached at the 4-position of the phenyl ring, and n is 2.
The invention also provides novel compounds of the following formula :
wherein R², R³, R⁴ and n are as previously defined and R⁶ and R⁷ are each NH₂ or N0₂, or R⁶ is (C₁-C₄ alkyl)S0₂NH and R⁷ is NH₂ or N0₂.
These compounds are valuable intermediates for the preparation of the antiarrhythmic compounds of formula (I).
The compounds of formula (I) are prepared from a compound of the formula :
wherein R², R³, R⁴ and n are as previously defined and R⁶ is NH₂ or (C₁-C₄ alkyl)S0₂NH-, by reacting with a C₁-C₄ alkyl sulphonylchloride or bromide, or a sulphonic anhydride of formula [(C₁-C₄ alkyl)SO₂]₂O.
The reaction is typically carried out by stirring the reactants together in an organic solvent at room temeprature for several hours. When a sulphonyl halide is used, the reaction is generally performed in pyridine but with a sulphonic anhydride, methylene chloride in a more suitable solvent. The product of formula (I) is isolated by removal of the solvent and purified by conventional procedures such as crystallisation or chromatography. In the case where R⁶ is NH₂, R¹ and R⁵ in the product of formula (1) will naturally be the same depending on the particular reagent used.
The starting materials of formula (III) wherein R⁸ is NH₂ are prepared from readily available starting materials as shown in the following reaction scheme wherein R², R³, R⁴ and n are as previously defined and Q is a good leaving group, for example Cl, Br, I, methanesulphonyloxy, phenylsulphonyloxy or para-toluenesul- phonyloxy ; bromine being generally preferred :
The initial reaction between the compounds offormula (IV) and (V) is typically achieved by heating the reactants in an organic solvent in the presence of an acid binding agent such as potassium carbonate. For example the reaction may be achieved by refluxing the reactants in acetonitrile for a period of one or two days. The product (VI) is then reduced, for example by catalytic hydrogenation over palladium on charcoal to yield the amine starting material of formula (III) wherein R⁸ is NH₂.
The starting compounds of formula (III) wherein R⁸ is (C₁-C₄ alkyl)S0₂NH are prepared as shown in the following reaction scheme wherein X is halogen, preferably chlorine and Q is a leaving group as previously defined :
The process involves reacting the amine of formula (VII) with, for example, an azido-O-methanesulphonyl alkanol to yield the azide (VIII) which is reduced by catalytic hydrogenation to give the amine (IX) wherein R³ is hydrogen. If desired, this product can be alkylated, for example by reaction with an alkyl halide, to give compounds of formula (IX) wherein R³ is C₁-C₄ alkyl.
In the next step, the reaction between the amine (IX) and the benzoyl halide (X) is typically carried out by stirring the reactants in equimolar proportions in an organic solvent, for example butan-2-one, either at room temperature or for a shorter period under reflux. The product (XI) is finally reduced as previously described to yield the starting material of formula (III) wherein R⁸ is (C₁-C₄ alkyl)SO₂NH. This route will of course be used when it is desired that R¹ and R⁵ in the product of formula (I) should be different
All of the above reactions are conventional and appropriate reagents and reaction conditions for their performance and procedures for isolating the desired products will be well known to those skilled in the art in accordance with literature precedents and by reference to the Examples hereto.
Pharmaceutically acceptable salts are readily prepared by mixing solutions containing equimolar amounts of the free base and the desired acid. The salt generally precipitates from solution or is recovered by evaporation of the solvent.
The biological activity of the compounds of the invention is assessed by measuring the effect of the compounds on atrial refractoriness. In this test guinea pig right hemiatria are mounted in a bath containing physiological salt solution, with one end connected to a force transducer. The tissues are stimulated at 1 Hz using field electrodes. Effective refractory period (ERP) is measured by introducing premature stimuli (S2) after every 8th basic stimulus (S₁)_' The S_lS₂ coupling interval is gradually increased until S₂ reproducibly elicits a propagated response. This is defined as the ERP. The test compound is then added to the bath and the concentration of compound required to increase ERP by 25% is determined (ED₂₅). ERP is also measured in guinea pig right papillary muscles incubated in physiological saline solution. Muscles are stimulated at one end using bipolar electrodes and the propagated electrogram is recorded at the opposite end via a unipolar surface electrode. ERP is determined as above using the extrastimulus technique. Conduction time is obtained from a digital storage oscilloscope by measuring the interval between the stimulus artefact and the peak of the electrogram (i.e. the time required for the impulse to travel along the length of the muscle).
Atrial and vetricular ERP's are also measured in anaesthetised or conscious dogs by the extrastimulus technique whilst the atrium or right ventricle is being paced at a constant rate.
For human use the compounds of the formula (I) can be administered alone but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. They can be administered both to patients suffering from arrhythmias and also prophylactically to those likely to develop arrhythmias. For example they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, forexample, enough salts or glucose to make the solution isotonic with blood.
For administration to man in the curative or prophylactic treatment of cardiac conditions such as ventricular and supraventricular arrhythmias, including atrial and ventricular fibrillation, it is expected that oral dosages of the compounds of the invention will be in the range from 1 to 75 mg daily, taken in up to 4 divided doses per day, for an average adult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules might contain 1 to 25 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration would be expected to be within the range 0.5 to 10 mg per single dose as required. A severe cardiac arrhythmia is preferably treated by the i.v. route in order to effect a rapid conversion to the normal rhythm. Variations on these dosages may occur depending on the weight and condition of the subject being treated as will be determined by the medical practitioner.
Thus the present invention provides a pharmaceutical composition comprising a compound of the formula (I) as defined above or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
The invention also provides a method of preventing or reducing cardiac arrhythmias in a human being, which comprises administering to said human an effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined above.
The invention yet further provides a compound of the formula (I) or pharmaceutically acceptable salt thereof, for use as an anti-arrhythmia agent.
The invention also provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or reduction of cardiac arrhythmias.
The preparation of the compounds of the invention, the intermediates of formula (II) and certain starting materials therefor are illustrated by the following Examples :

EXAMPLE 1

N-2-(Methylamino)ethyl-4-nitrobenzamide

4-Nitrobenzoyl chloride (8.2 g, 44 mmole) was added portionwise with simultaneous dropwise addition of 48% hydrobromic acid (11 ml, 135 mmole) to a stirred solution of N-methylethylenediamine (10 g, 135 mmole) in a mixture of ethanol (70 ml) and water (10 ml), maintaining the temperature below 40°C. The mixture was heated at reflux temperature for 1 hour, cooled, and stored at 5°C overnight. The precipitate was removed by filtration and the filtrate was evaporated to dryness. The residue was taken up in water, the acidity adjusted to pH 1.5 with hydrochloric acid and the solution chilled and filtered. The filtrate was basified with sodium hydroxide solution and extracted with methylene chloride (5 x 25 ml). The organic layers were combined, dried over sodium sulphate and evaporated. The residue was recrystallised from ethyl acetate to give the title compound (2.9 g 29%). m.p. 120-121°C. Found : C,53.8 ; H,5.9; N,18.7. C₁₀H₁₃N₃O₃ requires C,53.8 ; H,5.9 ; N,18.8%.

EXAMPLE 2

N-2-(Ethylamino)ethyl-4-nitrobenzamide

4-Nitrobenzoyl chloride (8.2 g, 44 mmole), 48% hydrobromic acid (11 ml, 135 mmole) and N-ethyl ethylenediamine (11.9 g, 135 mmole) were reacted following the procedure of Example 1 to give the title compound (3.0 g, 33%). m.p. 90-92°C. Found : C,55.5 ; H,6.4 ; N,17.6. C₁₁H₁₅N₃O₃ requires : C,55.7 ; H,6.4; N,17.7%.

EXAMPLE 3

N-[2-(N'-4-Nitrophenethyl-N'-methylamino)ethyl]-4-nitrobenzamide

N-2-(Methylamino)ethyl-4-nitrobenzamide (1.5 g, 6.7 mmole), 4-nitrophenethyl bromide (1.54 g, 6.7 mmole) and potassium carbonate (0.93 g, 6.7 mmole) in acetonitrile (50 ml) were stirred at reflux temperature for2 days. The solvent was evaporated and the residue diluted with water and extracted with methylene chloride (3 x 20 ml). The organic layer was washed twice with aqueous sodium carbonate and three times with brine, dried over sodium sulphate and evaporated. The resulting oil was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 2% by volume). The appropriate fractions were combined and the solvent evaporated to give the title compound (1.6 g, 64%). Found : C,58.0 ; H,5.3 ; N,14.95. C₁₈H₂₀N₄O₅ requires C,58.1 ; H,5.4 ; N,15.05%.

EXAMPLE 4

N-[2-(N'-4-Nitrophenethyl-N'-ethylamino)ethyl]-4-nitrobenzamide

N-2-(Ethylamino)ethyl-4-nitrobenzamide (2 g, 8.4 mmole), 4-nitrophenethyl bromide (1.94 g, 8.4 mmole), and potassium carbonate (1.17 g, 8.4 mmole) were heated in acetonitrile following the procedure of Example 3 to give the title compound (0.90 g). Found : C,58.75 ; H,5.90 ; N,14.3. C₁₉H₂₂N₄O₅ requires C,59.1 ; H,5.7 ; N,14.30%.

EXAMPLE 5

N-[2-(N'-4-Aminophenethyl-N'-methylamino)ethyl]-4-aminobenzamide

N-[2-(N'-4-Nitrophenethyl-N'-methylamino)ethyl-4-nitrobenzamide (1.2 g, 3.2 mmole) was stirred in ethanol with 5% palladium on charcoal (0.15 g), under a hydrogen atmosphere (3.45 bar) for 4 hours. The reaction mixture was filtered and the filtrate evaporated to dryness to give an oil, which was triturated with ethyl acetate and evaporated to give the title compound as a foam, (1.0 g, 99%) which was used without further purification. Found : C,67.9; H,7.9 ; N,17.0. C₁₈H₂₀N₄O₅.0.25 (CH₃CO₂C₂H₅) requires C,68.2; H,7.8; N,16.75%.

EXAMPLE 6

N-[2-(N'-4-Aminophenethyl-N'-ethylamino)ethyl]-4-aminobenzamide

N-[2-(N'-4-Nitrophenethyl-N'-ethylamino)ethyl-4-nitrobenzamide (0.85 g, 2.2 mmole) was hydrogenated following the procedure of Example 5 to give the title compound (0.48 g). ¹H-n.m.r. (CDCl₃) δ = 7.10 (q, 4H) ; 6.90 (q, 4H) ; 3.45 (q, 4H), 2.70 (m, 8H) ; 1.05 (t, 3H).

EXAMPLE 7

N-[2-(N'-4-Methanesulphonamidophenethyl-N'-methylamino)ethyl]-4-methanesulphonamidobenzamide, hemihydrate

Methanesulphonyl chloride (0.55 ml, 7.0 mmole) was added dropwise to a stirred solution of N-[2-(N'-4-aminophenethyl-N'-methylamino)ethyl]-4-aminobenzamide (0.9 g, 3.1 mmole) in pyridine (40 ml) at 0°C and the mixture stirred at room temperature for 18 hours. The solvent was removed by evaporation and the residue suspended in sodium bicarbonate solution which was extracted with methylene chloride (3 x 20 ml). The combined organic layers were washed twice with sodium bicarbonate solution and three times with brine, dried over sodium sulphate and evaporated to give an oil which was chromatographed on silica eluting with methylene chloride containing methanol (0% up to 5% by volume). The appropriate fractions were combined and evaporated to give the title compound as a colourless foam (0.60 g 43%). Found : C,50.65 ; H,6.1 ; N,11.6. C₂₀H₂₈N₄O₅S₂
H₂O requires C,50.3; H,6.1 ; N,11.7%.

EXAMPLE 8

N-[2-(N'-4-Methanesulphonamidophenethyl-N'-ethylamino)ethyl]-4-methanesulphonamidobenzamide

N-[2-(N_'-4-Aminophenethyl-N'-ethylamino)ethyl]-4-aminobenzamide (0.48 g, 1.47 mmole) was reacted with methanesulphonyl chloride (0.23 ml, 3.0 mmole) following the procedure of Example 7 to give the title compound (0.26 g). Found : C,51.9 ; H,6.4 ; H,11.4. C₂₁H₂₃N₄O₅S₂ requires C,52.3 ; H,6.3 ; N,11.6%.

EXAMPLE 9

N-[2-(N'-4-Methanesulphonamidophenethyl-N'-methylamino)ethyl]-2-methoxy-4-nitrobenzamide hemihydrate

1. 2-Azido-O-methanesulphonyl-ethanol

Methanesulphonyl chloride (5.7 g, 5 mmole) in methylene chloride solution was added dropwise over
hour to a stirred solution of 2-azidoethanol (4.3 g, 50 mmole) and triethylamine (5.0 g, 50 mmole) in methylene chloride (80 ml). After 2 hours the reaction mixture was washed with water, dried over magnesium sulphate and evaporated to dryness to give the title compound as a mobile oil (7.0 g).

2. 2-Azido-N-(4-methanesulphonamidophenethyl)-N-methyl-ethylamine

A mixture of N-(4-Methanesulphonamidophenethyl)methylamine (6.1 g, 26.8 mmole), 2-azido-O-methane sulphonyl-ethanol (4.4 g, 26.7 mmole) and sodium bicarbonate (5 g) in acetonitrile (100 ml) was heated at reflux temperature for 2.5 hours. The solvent was removed and the residue extracted with methylene chloride. The extract was filtered and the solvent evaporated. The residue was chromatographed on silica, eluting with methylene chloride containing methanol (from 0% up to 2% by volume). The appropriate fractions were combined and evaporated to give the title azide as an oil (5.4 g, 68%).

3. N-(4-Methanesulphonamidophenethyl)-N-methylethylenediamine

The above product (0.9 g, 33 mmole) in ethanol (50 ml) was stirred under an atmosphere of hydrogen (3.45 bar) at room temperature for 2 hours in the presence of 5% palladium on charcoal catalyst (0.1 g). The reaction mixture was filtered and evaporated to give the title diamine as a powder (0.51 g, 62%), m.p. 90-92°C. Found: C,52.8 ; H,7.8 ; N,15.2. C₁₂H₂₁N₃O₂S requires C,53.1 ; H,7.8 ; N,15.5%.

4.N-[2-(N'-4-Methanesulphonamidophenethyl-N'-methylamino)ethyl]-2-methoxy-4-nitrobenzamide hemihydrate

N-(4-Methanesulphonamidophenethyl)-N-methylethylenediamine (0.48 g, 1.9 mmole) and 2-methoxy-4-nitrobenzoyl chloride (0.4 g, 1.9 mmole) in butan-2-one were stirred at room temeprature for 4 hours and then heated at reflux temperature for 1 hour. The solvent was removed under reduced pressure and the residue diluted with aqueous sodium bicarbonate solution and extracted with methylene chloride (3 x 30 ml). The combined organic layers were washed three times with brine, dried over sodium sulphate and evaporated to an oil which was chromatographed on silica eluting with methylene chloride containing methanol (0% up to 2% by volume). The appropriate fractions were combined and evaporated to give the title compound as a foam, (0.51 g, 64%). Found : C,52.0 ; H,5.8 ; N,11.8. C₂₀H₂₈N₄O₈S.
H20 requires C,52.3 ; H,5.9 ; H,12.2%.

EXAMPLE 10

N-[2-(N'-4-Methanesulphonamidophenethyl-N'-methylamino)ethyl]-4-amino-2-methoxybenzamide

N-[2-(N'-4-Methanesulphonamidophenethyl-N'-methylamino)ethyl]-2-methoxy-4-nitrobenzamide (0.5 g, 1.19 mmole) was converted to the title compound by catalytic hydrogenation following the procedure of Example 5. Yield 0.45 g. ¹H-n.m.r. (CDCI₃) δ = 8.00 (d, 1H) ; 7.15 (q, 4H) ; 6.35 (q, 1H) ; 6.25 (d, 1H) ; 4.00 (s, 2H) ; 3.85 (s, 3H) ; 3.50 (q, 2H) ; 2.95 (s, 3H) ; 2.75 (d, 2H) ; 2.70 (d, 2H) ; 2.65 (q, 2H) ; 2.40 (s, 3H).

EXAMPLE 11

N-[2-(N'-4-Methanesulphonamidophenethyl-N'-methylamino)ethyl]-4-methanesulphonamido-2-methoxybenza mide

N-[2-(N'-4-Methanesulphonamidophenethyl-N'-methylamino)ethyl]-4-amino-2-methoxybenzamide (0.44 g, 1.0 mmole) was reacted with methanesulphonyl chloride (0.081 ml, 1.0 mmole) following the procedure of Example 7 to yield the title product (0.23 g, 47%). Found : C,50.5 ; H,6.05 ; N,11.0. C₂₁H₃₀N₄O₆S₂ requires C,50.8; H,6.1 ; N,11.2%.

Claims

1. A compound having the formula :

or a pharmaceutically acceptable salt thereof, wherein R¹ and R⁵ are each independently C₁-C₄ alkyl ;

R2 and R³ are each independently H or C₁-C₄ alkyl ;

R⁴ is H or C₁-C₄ alkoxy,
and n is 2,3 or 4.

2. A compound as claimed in claim 1 wherein R¹ and R⁵ are both CH₃.

3. A compound as claimed in claim 1 or claim 2 wherein R² is CH₃ or CH₂CH₃ and R³ is H.

4. A compound as claimed in any one of claims 1 to 3 wherein R⁴ is H or OCH₃.

5. A compound as claimed in any one of claims 1 to 4 wherein n is 2.

6. The compound of formula (I) wherein R¹ is CH₃, R² is CH₃, R³ is H, R⁴ is CH₃0 attached at the 2-position of the phenyl ring and R⁵ is CH₃, the group -NHSO₂R⁵ being attached at the 4-position of the phenyl ring, and n is 2.

7. A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6 together with a pharmaceutically acceptable diluent or carrier.

8. A compound of the formula (1) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6 for use in medicine, in particular for use as an anti-arrhythmia agent.

9. The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, for the manufacture of a medicament for the prevention or reduction of cardiac arrhythmias.

10. A compound of the formula :

wherein R², R³, R⁴ and n are as defined in claim 1 and R⁶ and R⁷ are each NH₂ or N0₂, or R⁶ is (C₁-C₄ alkyl)S0₂NH and R⁷ is NH₂ or NO₂.